Methylenetetrahydrofolate reductase genotypes and early-onset coronary artery disease

Background-Homozygosity for the common (677C-->T) mutation in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with hyperhomocystein emia, but there is uncertainty as to the association between this mutation and coronary artery disease (CAD). This study examined the association betw een MTHFR genotypes and age at onset of CAD. Methods and Results-Patients (n=169) with documented myocardial infarction or angiographically documented CAD who were aged less than or equal to 55 y ears at onset of CAD symptoms and DNA samples from control subjects (n=313) were studied. The prevalence of homozygosity among patients with early CAD onset (aged less than or equal to 45 years) was 28%, which was significant ly higher than that in patients with later onset (13%) and in control subje cts (14%) (odds ratio 2.4, 95% CI 1.24 to 4.69, P=0.006, and odds ratio 2.7 , 95% CI 1.15 to 6.42, P=0.01, respectively). Plasma folate was lower in TT homozygotes who had early CAD onset than in those with later onset (P=0.00 5). Among patients with plasma folate in the lowest quintile (less than or equal to 12.6 nmol/L), 31% were homozygotes, as were 45% of those with low plasma folate and early CAD onset. There was no difference in the prevalenc e of traditional risk factors among genotypes. The frequency of homozygosit y in patients with less than or equal to 1 risk factor was higher than in t hose with greater than or equal to 2 risk factors (30% versus 12%, P<0.05). In multiple regression analysis, TT homozygosity and plasma folate were in dependently associated with CAD, but the impact of folate was small. Conclusions-Homozygosity for the 677C-->T mutation of MTHFR is common and i s associated with an increased risk of premature CAD in this population.